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(Circulation. 1996;93:1658-1666.)
© 1996 American Heart Association, Inc.

Articles

Glucose Uptake in the Chronically Dysfunctional but Viable Myocardium

Maija Mäki, MD; Matti Luotolahti, MD; Pirjo Nuutila, MD; Hidehiro Iida, PhD; Liisa-Maria Voipio-Pulkki, MD; Ulla Ruotsalainen, MSc; Merja Haaparanta, MSc; Olof Solin, PhD; Jaakko Hartiala, MD; Risto Härkönen, MD; Juhani Knuuti, MD

From the Departments of Clinical Physiology (M.M., M.L., J.H.), Nuclear Medicine (M.M., M.L., R.H., J.K.), and Medicine (P.N., L.-M.V.-P.), the Medical Cyclotron-PET Center (U.R.), and the Radiopharmaceutical Chemistry Lab (M.H.), University of Turku, Finland; the Research Institute for Brain and Blood Vessels-Akita, Japan (H.I.); and the Accelerator Laboratory, Åbo Akademi University (O.S.), Turku, Finland.

	Abstract

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Background The regulation of glucose uptake in the dysfunctional but viable myocardium has not been studied previously in humans.

Methods and Results Seven patients with an occluded major coronary artery but no previous infarction were studied twice with 2-[¹⁸F]fluoro-2-deoxy-D-glucose positron emission tomography, once in the fasting state and once during hyperinsulinemic euglycemic clamping. Myocardial blood flow was measured with [¹⁵O]H₂O. The myocardial region beyond an occluded artery that showed stable wall-motion abnormality represented chronically dysfunctional but viable tissue. Six of the patients were later revascularized, and wall-motion recovery was detected in the corresponding regions, which confirmed viability. A slightly reduced myocardial blood flow was detected in the dysfunctional than in the remote myocardial regions (0.81±0.27 versus 1.02±0.23 mL·g^-1·min^-1, P=.036). In the fasting state, glucose uptake was slightly increased in the dysfunctional regions compared with normal myocardium (15±10 versus 11±10 µmol/100 g per minute, P=.038). During insulin clamping, a striking increase in glucose uptake by insulin was obtained in both the dysfunctional and the normal regions (72±22 and 79±21 µmol/100 g per minute, respectively; P<.001, fasting versus clamping).

Conclusions Contrary to previous suggestions, glucose uptake can be increased strikingly by insulin in chronically dysfunctional but viable myocardium. This demonstrates that insulin control over glucose uptake is preserved in the dysfunctional myocardium and provides a rational basis for metabolic intervention.

Key Words: glucose • myocardium • insulin • blood flow • coronary disease

	Introduction

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Glucose, lactate, and FFAs are the major sources of energy for the heart. In the fasting state, the myocardium predominantly uses FFAs, whereas in the fed state, glucose becomes more important.^{1 2} Striking changes occur in substrate utilization during myocardial ischemia. With the decline in oxygen delivery, oxidative metabolism decreases markedly but remains the predominant (>90%) source of residual ATP production.³ Since ß-oxidation of FFAs is very sensitive to ischemia, the principal fuel-contributing substrate for the citric acid cycle during ischemia is glucose.⁴ Additionally, glucose can yield energy anaerobically.^{3 5} Mild to moderate ischemia accelerates myocardial glucose uptake,⁶ but a minimum perfusion is required for the maintenance of glucose metabolism.^{7 8} It has been suggested^{6 9} that the viability of ischemic myocardium depends on glucose supply.

It has been proposed that prolonged regional wall-motion dysfunction in the noninfarcted myocardium results either from postischemic dysfunction (myocardial stunning)¹⁰ or from adaptation to chronic hypoperfusion (myocardial hibernation).¹¹ Myocardial stunning occurs when myocardial flow has normalized, whereas hibernation is thought to be a result of chronic ischemia. However, contractile function can be partially or completely restored to normal if the myocardial oxygen supply/demand relationship is favorably altered, eg, by improving tissue perfusion by revascularization.¹¹

Substrate metabolism and its regulation in the chronically dysfunctional but viable myocardium are poorly understood. With use of [¹⁸F]FDG and PET, glucose transport and phosphorylation can be estimated in humans in vivo.¹² The augmented glucose uptake indicated by enhanced [¹⁸F]FDG accumulation in hypoperfused and dysfunctional myocardial segments¹³ was suggested to represent the metabolic counterpart of hibernation.¹⁴ This increased [¹⁸F]FDG uptake relative to perfusion, the so-called blood flow–metabolism mismatch, also occurs in patients with stress-induced ischemia and unstable angina.¹⁵ It has been suggested^{14 16} that glucose uptake is fixed in the mismatch region and fails to respond to substrate availability and hormones. However, no previous studies have investigated the regulation of glucose uptake in chronically dysfunctional but viable myocardium.

The purpose of the present study was to measure glucose uptake and study whether glucose uptake in chronically dysfunctional but viable myocardium can be enhanced by insulin. We studied patients with an occluded major coronary artery and a chronic wall-motion abnormality but no previous myocardial infarction. Glucose uptake was measured twice by [¹⁸F]FDG and PET, once in the fasting state and once during euglycemic hyperinsulinemic clamping. MBF was measured with [¹⁵O]H₂O during clamping.

	Methods

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Subjects
The study group consisted of seven male patients (aged 62±9 years) with stable, angiographically confirmed coronary artery disease (Table 1). Six patients had total occlusion of the LAD and one had an occluded LCX. The regions distal to the occluded coronary arteries demonstrated chronic wall-motion abnormalities and were considered to represent chronically dysfunctional but viable myocardium in the present study. The patients had no previous history or ECG evidence of myocardial infarction, coronary artery bypass grafting, or coronary angioplasty. None of the patients had diabetes or was in overt heart failure. All patients were taking long-acting nitrates, four were taking ß-blockers, three took calcium antagonists, two took diuretics, and three used lipid-lowering agents. Six patients underwent coronary artery bypass grafting. One of the patients (patient 2) died before revascularization could be performed. Each subject gave written informed consent. The study protocol was accepted by the Ethical Committee of the Turku University Central Hospital, Finland.

View this table: [in this window] [in a new window]   Table 1. Patient Characteristics

Study Design
The angiographies were performed 2.7±1.7 months before the PET study. Radionuclide ventriculography was performed to determine left ventricular ejection fraction. The PET studies were performed after a 15- to 18-hour fast. Patients continued taking their normal medication during the study. The patients underwent two PET studies in random order on separate days within 2 weeks, once during insulin clamping and once in the fasting state (Fig 1). The clamping study consisted of a 150-minute period of hyperinsulinemia, whereas saline was infused into the patient in the fasting state. At 50 minutes of insulin clamping, MBF was measured. [¹⁸F]FDG was injected at 90 minutes, and dynamic scan was started. Echocardiograms were obtained immediately before and after each PET study. Heart rate and blood pressure were monitored during the studies to calculate the rate-pressure product. ECGs were monitored continuously during the PET studies. A follow-up echocardiography was performed 8±3 months after the operation to evaluate the potential wall-motion recovery.

View larger version (10K): [in this window] [in a new window]   Figure 1. The study protocol. Echo indicates two-dimensional echocardiography; St, static imaging; and Dyn, dynamic imaging.

Infusions and Blood Sampling
Two catheters were placed, one in an antecubital vein for infusion of saline or glucose and insulin and for injection of [¹⁸F]FDG and [¹⁵O]H₂O and another in a radial vein of the contralateral hand that was warmed (air temperature of 70°C) for sampling of arterialized venous blood. In the clamping study, an intravenous, primed, continuous insulin infusion was started as previously described.^{17 18 19} The rate of insulin infusion was 1 mU·kg^-1·min^-1. During hyperinsulinemia, euglycemia was maintained by infusing 20% glucose. The rate of the glucose infusion was adjusted according to plasma glucose concentrations measured every 5 to 10 minutes from arterialized venous blood. Blood samples were taken at 30-minute intervals for determination of insulin, FFA, and lactate concentrations. Catecholamines were determined once during each [¹⁸F]FDG imaging.

Measurement of MBF and Glucose Utilization by PET
Production of [¹⁵O]CO and [¹⁵O]H₂O
For production of ¹⁵O, a low-energy deuteron accelerator was used (Cyclone 3, Ion Beam Application Inc). [¹⁵O]CO was produced in a conventional way.^{20 15}O-labeled water was produced by use of dialysis techniques in a continuously working water module.²¹ Production rates for monoxide and water were 2.5 GBq/min and 1.7 GBq/min, respectively. Sterility and pyrogenicity tests for water and chromatographic analysis for gases were performed to verify the purity of the products.

Production of [¹⁸F]FDG
[¹⁸F]FDG was synthesized with an automatic apparatus by a modified method of Hamacher et al.²² The [¹⁸F]FDG had a specific activity >75 GBq/µmol at the end of synthesis and radiochemical purity >99%.

Image Acquisition, Processing, and Corrections
The patients were placed in a supine position in a 15-slice ECAT 931/08-12 tomograph (Siemens/CTI Inc) with a measured axial resolution of 6.7 mm and 6.5-mm planar resolution. To correct for photon attenuation, a transmission scan was performed for 20 minutes before emission scan with a removable ring source that contained ⁶⁸Ge (total counts, 15x10⁶ to 30x10⁶ per plane). In the beginning of the flow study, the subjects' nostrils were closed and they inhaled [¹⁵O]CO for 2 minutes through a three-way inhalation flap valve (0.14% CO mixed with room air; mean dose, 3850±740 MBq [104±20 mCi]). After the inhalation, 2 minutes was allowed to pass for carbon monoxide to combine with hemoglobin in red blood cells before a 4-minute static scan was started. During the scan period, three blood samples were drawn at 2-minute intervals, and blood radioactivity concentration was measured immediately with a well-type detector for natrium iodide with thallium impurities (Bicron 3MW3/3). After a 10-minute period for [¹⁵O]CO radioactive decay, 1630±220 MBq (44±6 mCi) of [¹⁵O]H₂O was injected intravenously over a 2-minute period and a 6-minute period of dynamic scanning was begun (6x5 seconds, 6x15 seconds, 8x30 seconds). Fifteen minutes later, 255±37 MBq (6.9±1.0 mCi) of [¹⁸F]FDG was injected intravenously over a 120-second period (259±19 MBq in the clamping study and 255±59 MBq in the fasting study; P=NS). Dynamic scan of the cardiac region was started simultaneously and lasted for 62 minutes (12x15 seconds, 4x30 seconds, 2x120 seconds, 1x180 seconds, 4x300 seconds, 3x600 seconds). Twenty-five blood samples were taken to measure [¹⁸F]FDG radioactivity in plasma. All data were corrected for dead time, decay, and photon attenuation and reconstructed in a 128x128 matrix. The final in-plane resolution in reconstructed and Hann-filtered (0.3 cycles/s) images was 9.5 mm full-width half maximum.

Calculation of Regional Glucose Utilization
A mean of 30 elliptical ROIs was placed on representative transaxial, ventricular slices in each study, with care taken to avoid myocardial borders. Plasma and tissue time-activity curves were analyzed graphically.²³ The slope of the plot in the graphic analysis is equal to the utilization constant (K_i) of [¹⁸F]FDG, which represents the fractional rate of tracer transport and phosphorylation. In the present study, the last seven time points were used to determine the slope by linear regression. The myocardium was divided into eight segments¹⁹ (anterobasal, anteroseptal, anterior, lateral, posteroseptal, apical, posterobasal, and inferior) and the mean K_i for each segment was calculated (average of 4 ROIs/segment). The rate of regional myocardial glucose uptake in each segment is given by

where P_gluc is mean plasma glucose level during imaging and LC (lumped constant) is used to correct for the differences in the transport and phosphorylation of [¹⁸F]FDG and glucose.^{24 25 26} LC was assumed to be 0.67.²⁴

Calculation of Regional Blood Flow
Values of regional MBF and water-perfusable tissue fraction were calculated segmentally according to the previously published method using the single-compartment model.^{27 28 29} The arterial input function was obtained from the left ventricular time-activity curve by use of a previously validated method³⁰ in which corrections were made for the limited recovery of the left ventricular ROI and spillover from the myocardial signals. Since glucose loading or insulin infusion at 1 mU·kg^-1·min ^-1 has been shown not to change MBF and its regional distribution,^{31 32} the MBF obtained during clamping was also used to represent flow in the fasting state in the present study.

Calculation of the Indexes for Metabolism and Flow
To estimate the relationship between metabolism and flow, glucose uptake–MBF ratios (corresponding glucose extraction) were calculated. Mismatch indexes were calculated by dividing the glucose uptake–MBF ratios obtained from dysfunctional myocardial regions by those obtained from normal myocardial regions.

Coronary Angiography
All patients underwent selective coronary angiography by standard techniques. Collateral circulation to the dysfunctional area was graded according to the following scale: 0, no visible collaterals; 1, poor (threadlike, poorly opacified distal arterial segment); 2, fair (good distal arterial segment, lightly and slowly opacified); and 3, adequate (good distal arterial segment, normally and quickly opacified).³³ The cine tapes were analyzed by an experienced radiologist.

Echocardiography
Two-dimensional echocardiography (Acuson 128XP/5, Acuson Inc or Aloka SSD 870, Aloka Inc) was performed according to the semiquantitative method recommended by the American Society of Echocardiography Committee on Standards,³⁴ but the segmental subdivision was modified to correspond to the PET studies.¹⁹ Echocardiograms were analyzed by a blinded, experienced physician (M.L.). The results of individual prerevascularization and postrevascularization echocardiograms were ultimately verified by comparison of videotape recordings. Wall motion and thickening were scored according to the following scale: 1, normal; 2, hypokinetic wall motion with systolic thickening; 3, akinetic wall motion with no systolic thickening; and 4, dyskinetic motion and no systolic thickening. The segments were considered to be thinned if wall thickness was reduced by >25% compared with the adjacent normal segments. Special efforts were made to detect any alterations in wall motion between the studies. After revascularization, improvement of contractile function was diagnosed if systolic thickening (corresponding to a score of 1 or 2) became apparent in a segment that had been akinetic or dyskinetic or if normal motion was detected in a previously hypokinetic segment. Improvement in function was acknowledged only if it was apparent in a central area of the segment. Special attention was focused on the anteroseptal segments because postsurgical wall-motion abnormalities are common in this area.³⁵ Thus, the appearance of postoperative anteroseptal hypokinesia was regarded as normal, and improvement was recognized only if systolic thickening became apparent in a previously akinetic or dyskinetic segment or if hypokinesia was normalized.

Radionuclide Ventriculography
A gated, blood-pool, radionuclide ventriculography was performed in two views. Six hundred cycles (10 minutes) were collected after injection of 740 MBq (20 mCi) of ^99mTc-labeled human serum albumin. The left anterior oblique view was used for ejection fraction calculations. A Siemens-Orbiter gamma camera (Siemens Gammasonics) was used, and ejection fractions were calculated with the Gamma-11 program (Nuclear Diagnostics).

Alignment of Myocardial Segments With Different Methods
Transaxial PET slices were visually aligned, and the results were assigned to the eight segments with the help of a heart-map phantom designed for our studies, as previously described.¹⁹ Wall-motion abnormalities in the echocardiograms were also localized in the segmental heart-map phantom. Angiographic data were assigned to the eight segments as follows: the LAD was suggested to supply anterobasal, anteroseptal, anterior, and apical regions; the LCX to supply lateral and posterobasal regions; and the RCA to supply posteroseptal and inferior segments. In two patients (patients 1 and 7), the LAD was occluded more distally; therefore, the anteroseptal segment supplied proximally to the stenosis was used as normal. In one patient (patient 5), the left obtuse marginal branch of the LCX was occluded and was assigned to the lateral segment. The posterobasal segment supplied by the LCX in that patient was regarded as normal (Table 2). The segmental scores for each method were finally aligned and pooled together (M.M. and J.K.).

View this table: [in this window] [in a new window]   Table 2. Functional and Metabolic Results by Segment in Dysfunctional and Normal Myocardial Regions Included in the Final Analysis

Analytical Procedures
Plasma glucose was determined in duplicate by the glucose oxidase method³⁶ with the use of an Analox GM7 (Analox Instruments Ltd) glucose analyzer. Serum insulin was measured by radioimmunoassay kit (Pharmacia) and serum FFAs by an enzymatic method (ACS-ACOD method, Wako Chemicals GmbH). Lactate was measured by enzymatic analysis.³⁷ Plasma epinephrine and norepinephrine were measured as previously described.³⁸

Statistical Analysis
All results are expressed as mean±SD. The difference between the dysfunctional and the remote regions, the changes from fasting to insulin-stimulated state, and the interaction of these two variables were tested statistically by use of ANOVA for repeated measures. A paired Student's t test was performed when appropriate. A value of P<.05 was interpreted as statistically significant. The statistical computation was performed with the SAS statistical program package (SAS Institute Inc).

	Results

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Metabolic and Physiological Characteristics During the Studies
Plasma glucose, lactate, epinephrine, and norepinephrine concentrations were comparable in the fasting state and during insulin clamping (Table 3). During clamping, serum insulin concentrations increased and were significantly higher than in the fasting state (P<.01). Serum FFA concentrations remained high in the fasting state but decreased by 90% during insulin infusion (P<.01). The rate-pressure products were similar during the two studies. Four patients had "fair" and three patients had "adequate" collateral circulation to the region of the occluded coronary artery according to the classification applied in the present study.³³ One patient (patient 7) experienced transient chest pain during the clamping study before PET imaging, but this resolved quickly with nitroglycerin. No ST-segment depression was detected during the studies.

View this table: [in this window] [in a new window]   Table 3. Metabolic and Physiological Characteristics During PET Studies

Regional Wall-Motion Abnormalities in Echocardiography
The affected myocardial segments were classified as hypokinetic in six of the seven patients. In one patient (patient 3), a large, akinetic region in the anterior wall with a small, apical, dyskinetic and thinned region was detected; the apical segment was excluded from further analysis because of potential previous myocardial injury. The mean number of dysfunctional segments per patient was 3±1 (range, 2 to 7 segments). Wall-motion abnormalities were stable in all patients in the four echocardiograms performed during the PET study periods. In the six revascularized patients, a follow-up echocardiogram was obtained 8±3 months after the operation. Wall motion recovered in all dysfunctional segments except the thinned apical segment in patient 3 (Table 2).

Segment Classification
For the purpose of the present study, angiographic and echocardiographic data were used to identify two types of myocardial segments as precisely as possible: (1) dysfunctional (collateral dependent) but viable or (2) normal. To avoid errors induced by misalignment, only segments with concordant results were accepted. A segment was classified as dysfunctional but viable when the corresponding coronary artery was occluded and a chronic wall-motion abnormality but no myocardial thinning was detected. The segment was classified as normal if it was associated with nonsignificant (50%) coronary artery stenosis and no wall-motion abnormalities. In each of two patients (patients 1 and 5), one segment associated with 75% stenosis in the corresponding coronary artery was accepted as normal because of severe coronary artery disease. The localization of segments included in the final analysis (n=29) is shown in Table 2. The remaining segments represented various combinations of abnormalities and were excluded from further analysis.

Dysfunctional segments were localized in the anterior wall in six patients and in the lateral wall in one patient. In all patients, a normal lateral (posterobasal in patient 5) wall segment was identified. In all but two patients (patients 3 and 6), a normal septal segment was also present. Since there were no differences in glucose uptake in the normal segments obtained from the lateral and septal regions in the fasting study or in the clamping study, the segments were pooled together and the mean values of the dysfunctional and all normal segments in each patient were calculated and used in the final analysis (Table 4).

View this table: [in this window] [in a new window]   Table 4. Summary of Functional, Metabolic, and Flow Results in Dysfunctional and Normal Myocardium

Visual Analysis of the PET Images
In the fasting state, dysfunctional segments manifested as "hot spots" in six of seven patients (Fig 2). In one patient, [¹⁸F]FDG uptake appeared homogeneous. During insulin clamping, [¹⁸F]FDG accumulation in the myocardium was qualitatively homogeneous in all patients (Fig 3) except patient 3, who had one excluded apical segment in which [¹⁸F]FDG uptake was reduced.

View larger version (157K): [in this window] [in a new window]   Figure 2. Transaxial 10-minute PET image obtained 50 minutes after FDG injection in the fasting state (patient 2). Increased FDG uptake is seen in the dyskinetic anterior wall.

View larger version (132K): [in this window] [in a new window]   Figure 3. Transaxial 10-minute PET image obtained 50 minutes after FDG injection during insulin clamping (same patient and comparable slice as in Fig 2).

Glucose Uptake in Dysfunctional and Normal Myocardium
Individual glucose uptake rates in dysfunctional and normal myocardium are shown in Table 4. In the fasting state, glucose uptake was slightly higher in dysfunctional than in normal regions in all but one patient (P=.038). A striking increase in glucose uptake by insulin was obtained in both region types (Fig 4; P<.001). During insulin clamping, glucose uptake rates were clearly within the normal range,¹⁹ although slightly lower values were detected in the dysfunctional regions (72±22 and 79±21 µmol/100 g per minute, respectively; P=.016).

View larger version (22K): [in this window] [in a new window]   Figure 4. Myocardial glucose uptake (MGU) in the fasting state and during insulin clamping in dysfunctional and normal segments. *P<.05; **P.001.

MBF in Dysfunctional and Normal Myocardium
MBF was lower in dysfunctional than in normal regions (0.81±0.27 versus 1.02±0.23 mL·g^-1·min^-1, respectively; P=.036; Table 4). However, flow in the dysfunctional regions was abnormally reduced only in half of the patients if relative MBF >80% is considered normal (Table 4). The fraction of water-perfusable tissue fraction was similar in the dysfunctional and normal regions (0.57±0.05 versus 0.62±0.03; P=NS). All patients had increased glucose uptake relative to flow (glucose uptake/MBF, or glucose extraction) in the fasting state in the dysfunctional area compared with normal myocardium (P=.013) (Table 4). Consequently, the mismatch index was 1.94±0.62. During insulin clamping, the average glucose uptake/MBF was also increased in dysfunctional tissue, but the difference was not statistically significant compared with the normal segments. In the clamping study, the mismatch index was 1.19±0.30.

	Discussion

Top Abstract Introduction Methods Results Discussion References

 
It has been suggested previously that glucose uptake in the ischemic and hibernating myocardium is fixed and fails to respond to alterations in substrate availability and hormones.^{14 16} In this investigation, we studied patients with an occluded major coronary artery and chronic wall-motion abnormalities but no previous myocardial infarction. In all dysfunctional regions, the perfusable tissue fraction was normal and wall-motion recovery was observed after revascularization, which indicates preserved myocardial viability. The results of the present study clearly show that insulin is able to stimulate myocardial glucose uptake in chronically dysfunctional but viable myocardium.

In the fasting state, slightly enhanced glucose uptake was found in dysfunctional regions compared with normal myocardium. This finding is consistent with earlier PET studies^{39 40} that demonstrated a hot spot in the mismatch regions during the fasting state. The enhanced [¹⁸F]FDG uptake cannot be explained by the physiological inhomogeneity of glucose uptake in the fasting state, since the hot spots primarily were located in the anterior wall, whereas glucose uptake normally is somewhat greater in the lateral or posterior wall.³¹ Insulin infusion caused a striking increase in glucose uptake in both dysfunctional and normal myocardial regions, and all dysfunctional regions showed that preserved glucose uptake clearly fell within the normal range.¹⁹

Prolonged regional wall-motion dysfunction in the noninfarcted myocardium has been proposed to result either from postischemic dysfunction (myocardial stunning) or from adaptation to chronic hypoperfusion (myocardial hibernation). Vanoverschelde et al³³ showed that blood flow in chronically dysfunctional, noninfarcted regions was only slightly less than in remote areas. Recently, permanent reduction of myocardial perfusion was found only in 20% of dysfunctional but viable regions, and the majority of the recovered segments were not chronically underperfused.⁴¹ Blood flow results obtained in the relatively small patient population in the present study are concordant with those two studies.

A distinct, segmental, metabolic abnormality with increased [¹⁸F]FDG uptake relative to blood flow, ie, blood flow–metabolism mismatch, is a classic observation in the PET studies of coronary patients.^{13 15 42} Augmented [¹⁸F]FDG uptake in hypoperfused and dysfunctional segments has been suggested to represent the metabolic counterpart of hibernating myocardium.¹⁴ In the present study, a clear mismatch pattern was detected in the fasting state. During insulin clamping, glucose uptake relative to flow was also greater in the dysfunctional myocardium, but the difference was not statistically significant. These findings are in line with previous clinical PET studies of myocardial viability.^{13 15 42}

The mechanism by which insulin increases glucose uptake in dysfunctional, noninfarcted tissue has not been demonstrated. In addition to the direct effects on glucose uptake and metabolism in cardiac myocytes, insulin effectively inhibits whole-body lipolysis and decreases circulating FFA concentrations.² We showed previously that high FFA concentrations inhibit myocardial glucose utilization,¹⁸ and acute reduction of arterial FFAs increases myocardial glucose uptake fivefold.⁴³ We also showed⁴⁴ that the effect of insulin on glucose uptake in the human heart in vivo and during physiological conditions is mediated mainly via inhibition of lipolysis, and the direct effects of insulin are of minor importance. This indirect mechanism of insulin action might also explain the preserved hormonal control in dysfunctional but viable myocardium. However, since [¹⁸F]FDG traces only the initial transport and phosphorylation of glucose, the fate of glucose in glycolysis or glycogen storage cannot be determined from the results of the present study.

Potential Clinical Implications
Providing glucose to the critically ischemic cell has been hypothesized to have multiple beneficial consequences, including inhibition of fatty acid metabolism, increased production of anaerobic ATP, and a protective effect on the threatened cell membrane.⁶ In terms of energy production, glucose is a more efficient fuel than FFAs.⁴⁵ Therefore, with limited oxygen reserve, oxidation of glucose can provide a greater yield of ATP. However, there is no clear consensus about the beneficial effects of glucose and insulin infusions during acute ischemia and infarction in humans.⁴⁶ The implications of enhanced glucose uptake in the chronically dysfunctional but viable myocardium are even less clearly understood. In the present study, no acute improvement in wall motion was observed with insulin infusion. The results of the present study show that myocardial metabolism and substrate utilization can be modified in the dysfunctional, noninfarcted myocardium, but the benefits of such an approach remain to be demonstrated.

Potential Study Limitations
The study patients were highly selected. We cannot be sure whether the results are also applicable to patients with ongoing ischemia, previous myocardial infarction, and severe heart failure. The patient population in the present study is similar to that in the study by Vanoverschelde et al,³³ in which metabolic and morphological correlates of chronically dysfunctional but viable myocardium were documented. We cannot rule out that the continuing anti-ischemic medication might have affected myocardial glucose uptake. However, the medication was kept unchanged during the study period. Because of severe coronary artery disease, a reference segment beyond a significant coronary artery stenosis (75%) was accepted in two patients. However, potential errors caused by this would diminish rather than increase the difference in glucose uptake between the dysfunctional and remote segments.

For glucose uptake calculations, we assumed that the LC remained unchanged in the fasting state and during insulin clamping. Previous studies²⁶ showed that the nutritional state does not affect LC. In intact canine hearts, glucose uptake rates measured with [¹⁸F]FDG were in good agreement with the direct determinations made by use of the Fick method over a wide range of glucose metabolic rates.²⁴ However, in the recent study by Hariharan et al,⁴⁷ an increase in insulin concentration did not increase [¹⁸F]FDG uptake in the isolated working rat heart, although [2-³H]glucose uptake was clearly enhanced, suggesting inconstancy of LC. In the present human study, insulin stimulated [¹⁸F]FDG uptake strikingly and to the same extent as previously detected with unlabeled glucose.³² Moreover, if [¹⁸F]FDG underestimates myocardial glucose uptake, the true increase of glucose uptake by insulin in the present study would be even more profound. We measured MBF with [¹⁵O]H₂O. Unlike other tracers such as ²⁰¹Tl or ¹³N-ammonia that measure average flow in the entire tissue region, [¹⁵O]H₂O measures flow only in the water-perfusable tissue. The water-perfusable tissue fraction was not decreased in the dysfunctional regions. Therefore, the tracer selection cannot explain the flow results of the present study.

Conclusions
In the chronically dysfunctional, noninfarcted myocardium, glucose uptake is slightly enhanced in the fasting state but, contrary to previous suggestions, can be strikingly increased by insulin. This demonstrates preserved control of insulin over glucose uptake in the dysfunctional but viable myocardium. Although chronic wall-motion abnormalities were detected in these regions, the quantitatively measured MBF was only mildly decreased. These findings challenge the current understanding of the pathophysiology and metabolism of the chronically dysfunctional but viable myocardium.

	Selected Abbreviations and Acronyms

 

FDG = 2-fluoro-2-deoxy-D-glucose FFA = free fatty acid Ki = the utilization constant of 2-[18F]fluoro-2-deoxy-D-glucose LAD = left anterior descending coronary artery LC = lumped constant LCX = left circumflex artery MBF = myocardial blood flow PET = positron emission tomography RCA = right coronary artery ROI = region of interest

	Acknowledgments

 
This study was supported by grants from the Novo Nordisk Foundation, Turku University Foundation, and Finnish Foundation for Cardiovascular Research. Our thanks go to the technicians in the Turku Cyclotron-PET Center, especially Riitta Fabritius, Anne-Mari Haanperä, Ritva Heikola, Tarja Keskitalo, Riitta Koskelin, Anne Mäkinen, Minna Mäkipää, Riitta Savonvirta, Maija Tuomi, and Marjo Tähti, for their skill and dedication throughout this study. We also express our gratitude to Tuula Niskanen, MSc, Hannu Sipilä, MSc, and Mika Teräs, MSc, for their excellent technical assistance and to Jorma Mikkola, MD, for analyzing the angiograms.

	Footnotes

 
Reprint requests to Maija Mäki, MD, Department of Nuclear Medicine and Turku Medical Cyclotron-PET Center, Turku University Central Hospital, FIN-20520 Turku, Finland.

Received September 25, 1995; revision received November 7, 1995; accepted November 19, 1995.

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